Research Spotlight

Cannon, J. A., L. Shen, P. S. Jhund, S. L. Kristensen, L. Kober, F. Chen, J. Gong, M. P. Lefkowitz, J. L. Rouleau, V. C. Shi, K. Swedberg, M. R. Zile, S. D. Solomon, M. Packer and J. J. McMurray (2016). “Dementia-related adverse events in paradigm-hf and other trials in heart failure with reduced ejection fraction.” Eur J Heart Fail: 2016 Nov [Epub ahead of print].

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AIMS: Inhibition of neprilysin, an enzyme degrading natriuretic and other vasoactive peptides, is beneficial in heart failure with reduced ejection fraction (HFrEF), as shown in PARADIGM-HF which compared the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan with enalapril. As neprilysin is also one of many enzymes clearing amyloid-beta peptides from the brain, there is a theoretical concern about the long-term effects of sacubitril/valsartan on cognition. Therefore, we have examined dementia-related adverse effects (AEs) in PARADIGM-HF and placed these findings in the context of other recently conducted HFrEF trials. METHODS AND RESULTS: In PARADIGM-HF, patients with symptomatic HFrEF were randomized to sacubitril/valsartan 97/103 mg b.i.d. or enalapril 10 mg b.i.d. in a 1:1 ratio. We systematically searched AE reports, coded using the Medical Dictionary for Regulatory Activities (MedDRA), using Standardized MedDRA Queries (SMQs) with ‘broad’ and ‘narrow’ preferred terms related to dementia. In PARADIGM-HF, 8399 patients aged 18-96 years were randomized and followed for a median of 2.25 years (up to 4.3 years). The narrow SMQ search identified 27 dementia-related AEs: 15 (0.36%) on enalapril and 12 (0.29%) on sacubitril/valsartan [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.33-1.59]. The broad search identified 97 (2.30%) and 104 (2.48%) AEs (HR 1.01, 95% CI 0.75-1.37), respectively. The rates of dementia-related AEs in both treatment groups in PARADIGM-HF were similar to those in three other recent trials in HFrEF. CONCLUSION: We found no evidence that sacubitril/valsartan, compared with enalapril, increased dementia-related AEs, although longer follow-up may be necessary to detect such a signal and more sensitive tools are needed to detect lesser degrees of cognitive impairment. Further studies to address this question are warranted.

Copeland, L. A., E. P. Finley, M. J. Bollinger, M. E. Amuan and M. J. Pugh (2016). “Comorbidity correlates of death among new veterans of iraq and afghanistan deployment.” Med Care 54(12): 1078-1081.

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BACKGROUND: Veterans of the wars in Iraq and Afghanistan who receive care in the Veterans Health Administration (VA) have high disease burden. Distinct comorbidity patterns have been shown to be differentially associated with adverse outcomes, including death. This study determined correlates of 5-year mortality. MATERIALS AND METHODS: VA demographic, military, homelessness, and clinical measures informed this retrospective analysis. Previously constructed comorbidity classifications over 3 years of care were entered into a Cox proportional hazards model of death. RESULTS: There were 164,933 veterans in the cohort, including African Americans (16%), Hispanics (11%), and whites (65%). Most were in their 20s at baseline (60%); 12% were women; 4% had attempted suicide; 4% had been homeless. Having clustered disorders of pain, posttraumatic stress disorder, and traumatic brain injury was associated with death [hazard ratio (HR)=2.0]. Mental disorders including substance abuse were similarly associated (HR=2.1). Prior suicide attempt (HR=2.2) or drug overdose (HR=3.0) considerably increased risk of death over 5 years. CONCLUSIONS: As congressional actions such as Veterans Choice Act offer more avenues to seek care outside of VA, coordination of care, and suicide prevention outreach for recent veterans may require innovative approaches to preserve life.

Desnick, R. J., N. W. Barton, S. Furbish, G. A. Grabowski, S. Karlsson, E. H. Kolodny, J. A. Medin, G. J. Murray, P. K. Mistry, M. C. Patterson, R. Schiffmann and N. J. Weinreb (2016). “Roscoe owen brady, md: Remembrances of co-investigators and colleagues.” Mol Genet Metab: 2016 Nov [Epub ahead of print].

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To celebrate the research visions and accomplishments of the late Roscoe O. Brady (1923-2016), remembrance commentaries were requested from several of his postdoctoral research fellows and colleagues. These commentaries not only reflect on the accomplishments of Dr. Brady, but they also share some of the backstories and experiences working in the Brady laboratory. They provide insights and perspectives on Brady’s research activities, and especially on his efforts to develop an effective treatment for patients with Type 1 Gaucher disease. These remembrances illuminate Brady’s efforts to implement the latest scientific advances with an outstanding team of young co-investigators to develop and demonstrate the safety and effectiveness of the first enzyme replacement therapy for a lysosomal storage disease. Brady’s pursuit and persistence in accomplishing his research objectives provide insights into this remarkably successful physician scientist who paved the way for the development of treatments for patients with other lysosomal storage diseases.

Gandhi, S. S., J. V. Blas, S. Lee, J. F. Eidt and C. G. Carsten, 3rd (2016). “Nonoperative management of grade iii blunt thoracic aortic injuries.” J Vasc Surg 64(6): 1580-1586.

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OBJECTIVE: Blunt thoracic aortic injuries (BTAIs) have historically been treated with open surgery; thoracic endovascular aortic repair (TEVAR), however, is rapidly becoming the standard of care for all grades of injury. Previous studies have shown successful, conservative management of low-grade (I and II) BTAI, but limited literature exists regarding nonoperative management (NOM) for high-grade BTAI. The purpose of this study was to evaluate NOM for grade III BTAI compared with TEVAR. METHODS: There were 75 patients diagnosed with BTAI between January 2004 and June 2015. Of these, 40 were excluded for different grades of BTAI (17), death before any treatment (6), and need for urgent open repair (17). The remaining 35 patients were divided into two groups by treatment approach: NOM (n = 18) and TEVAR (n = 17). Primary end points were complications and mortality. The secondary end point was difference in pseudoaneurysm and aortic diameter measurements between groups. RESULTS: The groups of patients were similar in age, gender, Injury Severity Score, length of stay, in-hospital mortality, and hospital-associated complications. There were four TEVAR-related complications: graft involutions (2), type I endoleak (1), and distal embolization (1). All TEVAR-related complications required either an adjunctive procedure at the time of the primary procedure or an additional procedure. No patients from the NOM group required operative intervention. There were seven in-hospital mortalities: two in the TEVAR group (11.8%) and five in the NOM group (27.8%; P = .402). One death in the NOM group was related to aortic disease. Follow-up computed tomography imaging revealed similar aortic-related outcomes between groups, with a high proportion showing resolved or improved aortic injury (NOM, 87.5%; TEVAR, 92.9%; P = .674). Initial computed tomography imaging showed similar aortic diameters between groups. The average diameter of the aorta distal to the subclavian artery was 22.6 mm in the NOM group vs 22.8 mm in the TEVAR group (P = .85). The average maximum diameter of the pseudoaneurysm was 30.1 mm in the TEVAR group and 29.9 mm in the NOM group (P = .90). The average ratio of diameter of the pseudoaneurysm to diameter of the aorta distal to the subclavian artery was 1.32 for the TEVAR group and 1.33 for the NOM group (P = .85). CONCLUSIONS: The natural history of grade III BTAIs is not well described. This study suggests that observation and NOM of grade III BTAI may be a reasonable therapeutic option in selected patients. It also speaks to the need for further delineation of the natural history of this injury. Serial imaging and long-term follow-up are necessary to monitor the progression of the pseudoaneurysm.

Haskins, I. N., J. W. Fleshman, R. L. Amdur and S. Agarwal (2016). “The impact of bowel preparation on the severity of anastomotic leak in colon cancer patients.” J Surg Oncol 114(7): 810-813.

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BACKGROUND AND OBJECTIVES: The routine use of preoperative bowel preparation (BP) is heavily debated in the colorectal surgery literature. To date, no study has investigated the effect preoperative BP has on patients with an established anastomotic leak. We therefore seek to compare the severity of patient morbidity and mortality in patients with a known anastomotic leak based on type of preoperative BP using the Targeted Colectomy American College of Surgeons National Surgery Quality Improvement Program (ACS-NSQIP). METHODS: All elective colon cancer operations performed with primary anastomosis were identified within the targeted colectomy database from 2012 to 2013. Patients who experienced a postoperative anastomotic leak were identified and stratified based on preoperative BP. Variables that had an association with mechanical BP at P < 0.10 were included in a multivariate logistic regression model to determine if BP was independently associated with postoperative morbidity and mortality. RESULTS: A total of 6,297 patients underwent elective colon resection with primary anastomosis for colon cancer. Two hundred and nineteen (3.5%) patients experienced an anastomotic leak. Thirty-day wound morbidity and mortality was not worse in patients who underwent preoperative BP. CONCLUSIONS: BP is not associated with worse patients outcomes in those patients with an established anastomotic leak following elective colon research with primary anastomosis.